Component B as cicatrizant

ABSTRACT

The present invention relates to the use of Component B as cicatrizant, in particular in the treatment of wounds, ulcers and other traumatic lesions to any of the tissues in the body.

This is a 371 of PCT/EP96/01702 filed Apr. 24, 1996.

The present invention relates to the use of Component B as cicatrizant, in particular in the treatment of wounds, ulcers and other traumatic lesions to any of the tissues in the body.

Component B is a 81-amino acid protein originally isolated from human urine. The human gene has been cloned and expressed in CHO cells as recombinant human Component B. The molecule has a molecular weight of about 8.9 kD. It has been thoroughly described in WO 94/14259.

Such protein contains ten cysteines and bears a motif typical of serine protease enzymes. Sequence alignment to a protein data bank has shown some homologies of Component B with known molecules such as CD59, urokinase receptor (uPA-R) and some venom toxins.

Data obtained by the Applicant from the study of organ and tissue distribution in mice showed that eye, lung and skin are the sites in which Component B RNA is mainly expressed. In human tissues, Component B was found to be highly expressed in the squamous epithelia and mucosae, such as skin, oesophagus and exocervix, as determined by immunohistochemistry. Finally, EGF has been found to induce the expression of Component B RNA in human squamous epidermoid A431 cells.

Component B has been reported to have antiinflammatory, anticoagulant and antitumoral activity, as well as an activity as inihibitor of the binding of TGF-α to its receptor.

The Applicant has now found that Component B is also useful as cicatrizant, and it is, therefore, in particular, useful in the treatment of wounds, ulcers and other traumatic lesions to any of the tissues in the body.

Therefore, the main object of the present invention is the use of Component B for the manufacture of a pharmaceutical composition useful as cicatrizant, in particular in the treatment of wounds, ulcers and other traumatic lesions to any of the tissues in the body.

A further object of this invention is a method of treatment of wounds, ulcers and other traumatic lesions to any of the tissues in the body, comprising administering an effective amount of Component B, together with a pharmaceutically acceptable excipient.

Another object of the invention are pharmaceutical compositions prepared as described above.

For the methods of preparation of Component B and for its amino acid sequence, reference is made to the disclosure of WO 94/14259.

The administration of the active ingredient may be by oral, intravenous, intramuscular, subcutaneous or topical route. Other routes of administration, which may establish the desired blood levels of the respective ingredients, are comprised by the present invention.

For the human therapy the preferred doses are 1 mg/kg or less for the systemic administration and 4 μg/cm² or less for the topical administration.

The invention will now be described by means of the following Examples, which should not be construed as in any way limiting the present invention. The Examples will refer to the Figures as specified here below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: the effect of the intravenous administration of Component B in comparison with that of betametasone (Bentelan®) on the experimental wound healing is shown. In particular, the results of Experiment 1 are summarised. Test drugs were administered daily for 6 consecutive days from day 0 (the day of wound induction) through 5.

FIG. 2: the effect of the intravenous administration of Component B (batch 004-001b) in comparison with that of betametasone (Bentelan®) on the experimental wound healing is shown. In particular, the results of Experiment 2 are summarised. Test drugs were administered daily for 6 consecutive days from day 0 (the day of wound induction) through 5.

FIG. 3: the effect of the topical application of Component B (batch 004-001) on the experimental wound healing is shown. In particular, the results of Experiment 3 are summarised. Test drugs were topically applied for 5 consecutive days from day 0 (the day of wound induction) through 4.

FIG. 4: the effect of the topical application of bovine serum albumin on the experimental wound healing is shown. In particular, the results of Experiment 4 are summarised. Test drugs were topically applied for 5 consecutive days from day 0 (the day of wound induction) through 4.

FIG. 5: the sigmoidal dose response analysis applied to the results of Experiment 1 is reported. The effect of the intravenous administration of Component B (batches 004-001 and 004-001b, indicated as "001" and "001b", respectively) and betametasone (Bentelan ®) on the experimental wound healing is, therefore, statistically evaluated on the basis of the results of Experiment 1.

FIG. 6: the sigmoidal dose response analysis applied to the results of Experiment 2 is reported. The effect of the intravenous administration of Component B (batch 004-001b, indicated as "001b") and betametasone (Bentelan®) on the experimental wound healing is, therefore, statistically evaluated on the basis of the results of Experiment 2.

FIG. 7: the sigmoidal dose response analysis applied to the cumulated results of Experiments 1 and 2 is reported. The effect of the intravenous administration of Component B (batch 004-001b) on the experimental wound healing is, therefore, statistically evaluated on the basis of the combination of the results of Experiments 1 and 2.

FIG. 8: the sigmoidal dose response analysis applied to the cumulative frequency, relative to combination of Experiments 1 and 2 is reported. The effect of Component B (batch 004-001b) is so evaluated.

FIG. 9: the sigmoidal dose response analysis applied to the results of Experiment 3 is reported. The effect of the topical and intravenous administration of Component B (batch 004-001) on the experimental wound healing is, therefore, statistically evaluated on the basis of the results of Experiment 3.

FIG. 10: the sigmoidal dose response analysis applied to the results of Experiment 4 is reported. A comparison of the effect between buffer and BSA in wound reduction is, therefore, statistically evaluated on the basis of the results of Experiment 4.

EXAMPLES Materials

Animals

SPF CD-1 mice of both sexes, purchased from Charles River Italia (Calco, Como, Italy), were used for the experiments after an acclimatisation period of at least seven days under controlled environmental conditions (temperature 22±2° C.; humidity: 55±10% and a light/dark cycle of 12 hours).

Test compounds

rec-hComponent B batch 004-001 (sulphated form) and 004-001b (non-sulphated form) expressed in CHO cells and produced essentially as described in WO 94/14259.

Commerical preparation of betametasone (Bentelan®) from Glaxo (Verona, Italy).

Sodium chloride 0.9% (saline), from Baxter (Trieste, Italy).

Bovine serum albumin (BSA), fraction V supplied by Sigma Chemical Co. (St. Louis Mo., USA).

Methods

Experimental full-thickness wound healing

The method used was that suggested by J. J. P. Morton and M. H. Malone (Morton J. J. P. and Malone M. H., Arch. Int. Pharmacodyn. 196: 117, 1972), who used this procedure for the evaluation of a number of drugs for their vulnerary activity in rats.

For the present study of Component B, the original method was suitably modified to be used in mice, as follows.

A circular ink mark (1 cm diameter) was impressed on the dorsal region of male mice (30-35 g, 6-7 week-old), and the skin of this marked area (including panniculus carnosus and adherent tissues) was excised using surgical scissors and forceps. The wound was then blotted dry with gauze pads until haemostasis occurred. On day 0, i. e. the day of surgery, longitudinal, transverse and two diagonal measurements (relative to the vertebral column) were made of the diameter of the wound to the nearest 0.1 mm using a direct reading caliper. The exact points of measurements were preserved by marking the adjacent skin with indelible ink. Subsequent wound measurements were made every other day except on Sunday up to complete wound closure. Both surgery and measurements were made under light ether anaesthesia of the mice.

The area of each wound was obtained by multiplying the square of its mean diameter by 0.7854. Per cent wound closure was then calculated relative to day 0. The mean per cent wound closure values for each measurement day were tabulated for each experimental group and the closure time 50% (CT₅₀) interpolated.

Systemic treatment

Two experiments (Experiments 1 and 2) were performed. In the second experiment, on each measurement day, the measurements were performed by the same operator who was unaware of the treatment schedules. In each experiment the animals were divided into 4 groups and treated according to the following schedule.

    ______________________________________                                         Group number                                                                            1st experiment  2nd experiment                                        ______________________________________                                         1        Saline 10 ml/kg, i.p.                                                                          Saline 10 ml/kg, i.v.                                 2        Component B 004-001,                                                                           Component B 004-001b,                                          1 mg/kg, i.v.   0.1 mg/kg, i.v.                                       3        Component B 004-001b,                                                                          Component B 004-001b,                                          1 mg/kg, i.v.   1 mg/kg, i.v.                                         4        Betametasone, 1 mg/kg, i.p.                                                                    Betametasone, 1 mg/kg, i.v.                           ______________________________________                                    

The animals were treated once a day for 6 consecutive days. The body weight of the animals was monitored for the whole duration of the study.

Topical treatment

In a further experiment (Experiment 3) the effect of the topical application of different doses of Component B (batch 004-001) were studied by using the already described procedure for wound induction following the treatment schedule reported in the table herebelow.

    ______________________________________                                         Group number  Treatment                                                        ______________________________________                                         1             Phosphate buffer 0.05 ml, topically                              2             Component B 004-001, 1 μg, topically                          3             Component B 004-001, 2 μg, topically                          4             Component B 004-001, 4 μg, topically                          5             Component B 1 mg/kg, i.v.                                        ______________________________________                                    

The solutions of the test product were applied (volume 0.05 ml) onto the wounds on days 1 and 2, whereas in the successive days, when the scab had been formed, they were injected underneath the scab by a syringe equipped with a 25 G needle.

Component B administered i.v. at the dose of 1 mg/kg, has been used as positive reference standard.

To rule out the possibility of aspecific effects of topical application of a proteic solution, in a parallel experiment the effect of BSA, at the same molar concentrations (8.8×10⁻⁶ M) as Component B, was assayed topically in comparison to phosphate buffer (Experiment 4).

Results

Wound healing

FIG. 1 reports the data of the first Experiment, in which the activity of two batches (004-001 and 004-001b) of Component B were compared. Both of them were capable of accelerating the cicatrization process, their effects being already evident after 1 day of treatment. CT₅₀, i.e. the time when 50% wound reduction occurs, is 3.0 and 3.4 days, respectively, these values being not statistically different. By contrast, CT_(50's) of 7.8 and 7.2 days were observed with betametasone (Bentelan®) and saline, respectively (see the paragraph entitled "Statistical Analysis").

In the second Experiment (FIG. 2) two doses of Component B (batch 004-001b) were studied. At the highest dose, 1 mg/kg, the CT₅₀ was 3.7 days whereas it was of 6.6 days at the lowest dose (0.1 mg/kg). The saline and betametasone treated groups displayed CT₅₀ 's of 9.1 and 10 days, respectively (see the paragraph entitled "Statistical Analysis").

The positive effect of Component B on wound healing was also confirmed by another index, namely ET₅₀, indicating the time when 50% of the animals showed complete wound closure (see the paragraph entitled "Statistical Analysis").

The results of the experiment where Component B (batch 004-001) was applied topically onto the wound (Experiment 3), are reported in FIG. 3. The compound was studied at doses of 1, 2 and 4 μg/day for 5 consecutive days. All doses assayed were capable of enhancing the wound healing process as compared to controls. In particular, doses of 2 and 4 μg provided CT₅₀ values of 3.8 and 4.4, respectively, which are comparable to that found (3.9) with 1 mg/kg of Component B given i.v. With the lowest dose (1 μg), a CT₅₀ value of 5.3 days was observed, which is higher than those obtained with the other two topical doses, but still significantly different from controls (see the paragraph entitled "Statistical Analysis").

These data suggest that a dose of 2 μg, topically applied on the wound, produces the maximal effect and that 1 μg is still effective in enhancing the cicatrization process.

In order to verify whether the positive effect of Component B on the wound healing process is a specific characteristic of the product, a parallel experiment was carried out, in which the effect of BSA, at the same molar concentration of Component B, was compared to that of phosphate buffer (Experiment 4). These data are reported in FIG. 4. CT₅₀ 's of 9.9 and 7.9 days were recorded with BSA and phosphate buffer, respectively. The above values are not significantly different (see the paragraph entitled "Statistical Analysis"), thus indicating that a standard protein solution, like BSA, does not influence the cutaneous wound repair.

The individual data of these experiments were reported in Tables 1A-4B.

Statistical Analysis

Statistical strategy

The statistical analysis was aimed at comparing the effect over the time of two preparations of Component B (Comp. B) both vs saline and the reference drug Bentelan.

Furthermore, the effects of the systemic and the topical administration of one preparation of Component B have been also evaluated.

In accordance with the treatment protocol the effect of the test drugs was studied considering the entire observation period.

The wound reduction experiment was repeated twice in order to confirm the Comp B effect at different dose levels.

Statistical test

The Sigmoidal Dose Response Analysis for the evaluation of the CT₅₀ (i.e. the time when the wound area is reduced by 50%) was used as the statistical test (see Finney D. J., Biometrics, 32, pp. 721-40, 1976).

Statistical units

1) Wound reduction (CT₅₀): Average percentage of variation vs average basal values.

2) Cumulative Frequency (ET₅₀): Cumulative frequency of animals showing a complete wound closure at each time point.

Groups of treatment (Exp. No 1)

1-Saline--10 ml/kg/day, i.p. for 6 days

2-Bentelan--1 mg/kg/day, i.p. for 6 days

3-CompB 004-001--1 mg/kg/day, i.v. for 6 days

4-CompB 004-001b--1 mg/kg/day, i.v. for 6 days

Groups of treatment (Exp. No 2)

1-Saline--10 ml/kg/day, i.v. for 6 days

2-Bentelan--1 mg/kg/day, i.v. for 6 days

3-CompB 004-001b--0.1 mg/kg/day, i.v. for 6 days

4-CompB 004-001b--1 mg/kg/day, i.v. for 6 days

Groups of treatment (Exp. No 3)

1-Phosphate buffer--50 μl/day, topical for 5 days

3-CompB 004-001--1 μg/day, topical for 5 days

3-CompB 004-001--2 μg/day, topical for 5 days

4-CompB 004-001--4 μg/day, topical for 5 days

5-CompB 004-001--1 mg/kg/day, i.v. for 5 days

Groups of treatment (Exp. No 4)

1-Phosphate buffer--50 μl/day, topical for 5 days

2-Bovine serum albumin (BSA)--50 μl/day (8.8×10⁻⁶ M), topical for 5 days

Treatment schedule (for Experiments 1, 2, 3 and 4)

Phase 1: Repeated treatment days according to the above treatment-group description.

Phase 2: Observation period up to the day of complete wound closure.

Results of the Statistical Analysis

The diagrams (sigmoidal dose response analysis) reported in FIGS. 5-10 summarise the effect of the test drugs as the variable the wound area.

Experiment 1

Reference is made to FIG. 5.

The results of the sigmoidal dose response analysis (CT₅₀) applied to the wound area, relative to experiment 1, are reported in the following table.

    ______________________________________                                         Test Drug      CT.sub.50 (days)                                                                         Confidence Limits                                                                           R.sup.2                                  ______________________________________                                         Saline         7.2       6.2-8.3      0.96                                     Bentelan 1 mg/kg                                                                              7.8       6.9-8.8      0.97                                     CompB 004-001 1 mg/kg                                                                         3.0       2.5-3.7      0.97                                     CompB 004-001b 1 mg/kg                                                                        3.4       2.8-4.1      0.97                                     ______________________________________                                    

Experiment 2

Reference is made to FIG. 6.

The results of the sigmoidal dose response analysis (CT₅₀) applied to the wound area, relative to experiment 2 are reported in the following table.

    ______________________________________                                         Test Drug      CT.sub.50 (days)                                                                         Confidence Limits                                                                           R.sup.2                                  ______________________________________                                         Saline         9.1       8.4-9.9      0.98                                     Bentelan 1 mg/kg                                                                              10.0       9.6-10.4    0.99                                     CompB 004-001b 0.1 mg/kg                                                                      6.6       5.5-7.7      0.94                                     CompB 004-001b 1 mg/kg                                                                        3.7       2.8-4.8      0.92                                     ______________________________________                                    

Combination of Experiments 1 and 2

Reference is made to FIG. 7.

The results obtained from the combination of the data of treatment groups common to both experiments 1 and 2, i.e. saline vs CompB-004-001b 1 mg/kg are summarised.

In addition, the frequency over the time of the animals showing complete closure of the wound was also evaluated (by Sigmoidal Dose-Response Analysis) from the cumulated data of Experiments 1 and 2.

The results of the sigmoidal dose response analysis (CT₅₀) applied to the wound area, relative to the combination of experiments 1 and 2, are reported in the following table.

    ______________________________________                                         Test Drug      CT.sub.50 (days)                                                                         Confidence Limits                                                                           R.sup.2                                  ______________________________________                                         Saline         8.2       7.5-8.9      0.95                                     CompB 004-001b 1 mg/kg                                                                        3.5       3.0-4.1      0.95                                     ______________________________________                                    

For the cumulative frequency, reference is made to FIG. 8.

The results of the sigmoidal dose response analysis (ET₅₀) applied to the cumulative frequency, relative to the combination of experiments 1 and 2, are reported in the following table.

    ______________________________________                                         Test Drug      ET.sub.50 (days)                                                                         Confidence Limits                                                                           R.sup.2                                  ______________________________________                                         Saline         16.1      15.4-16.9    0.98                                     CompB 004-001b 1 mg/kg                                                                        11.7      11.2-12.1    0.99                                     ______________________________________                                    

In conclusion, the comparison among CT₅₀ values and among ET₅₀ values is a good estimate of the effect of each test drug on the experimental model.

Both CompB-001 (1 mg/kg, i.v.) and CompB-001b (dose levels 0.1 mg/kg and 1 mg/kg, i.v.) were found to be statistically different from saline and Bentelan in Experiments 1 and 2. The results of the combination of treatment groups common to Experiments 1 and 2 confirm the effect of the i.v. route of administration with CompB 1 mg/kg.

Experiment 3

Reference is made to FIG. 9.

A further set of experiments was performed in which the product was topically applied. The intravenous route was used as positive reference standard. The data were analysed using the same statistical models as above.

The results of the sigmoidal dose response analysis (CT₅₀) applied to the wound area, relative to experiment 3, are reported in the following table.

    ______________________________________                                         Test Drug      CT.sub.50 (days)                                                                         Confidence Limits                                                                           R.sup.2                                  ______________________________________                                         Phosphate Buffer                                                                              8.3       7.3-9.5      0.96                                     CompB-001 1 mcg topical                                                                       5.3       4.1-6.9      0.91                                     CompB-001 2 mcg topical                                                                       3.8       2.9-4.9      0.92                                     CompB-001 4 mcg topical                                                                       4.4       3.4-5.6      0.92                                     CompB-001 1 mg/kg i.v.                                                                        3.9       3.0-5.2      0.92                                     ______________________________________                                    

In conclusion, topical administration of CompB-001b showed, at all doses tested, a wound reduction (CT₅₀) significantly different from phosphate buffer.

Experiment 4

Reference is made to FIG. 10.

The diagram reports the comparison between topical application of phosphate buffer and BSA in wound reduction in order to rule out possible aspecific effects of Component B.

The results of the sigmoidal dose response analysis (CT₅₀) applied to the wound area, relative to Experiment 4, are reported in the following table.

    ______________________________________                                         Test Drug                                                                               CT.sub.50 (days)                                                                            Confidence Limits                                                                           R.sup.2                                     ______________________________________                                         Buffer   7.9          7.2-8.7      0.98                                        BSA      9.9          8.5-11.4     0.95                                        ______________________________________                                    

The above results did not show any differences between the topical application of phosphate buffer and BSA.

Conclusions of all the Study

The interesting result of this study is the activity of Component B in the cicatrization process both when administered intravenously or by topical application. The experimental model used in this study is directly related to the human trauma counterpart and is predictive for the application of Component B in the healing of traumatic lesions of the skin and in plastic and reconstructive surgery of mucosae and epithelia.

                                      TABLE 1A                                     __________________________________________________________________________     Wound healing data - Experiment 1                                              Comp B 004-001: 1 mg/kg, i.v.                                                  __________________________________________________________________________     Day 0                                                                               Day 1   Day 3    Day 5    Day 7                                           area area                                                                              % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                   __________________________________________________________________________     0.622                                                                               0.529                                                                             -14.9518                                                                            0.318                                                                              -48.8746                                                                            0.135                                                                              -78.2958                                                                            0.06                                                                               -90.3537                                    0.813                                                                               0.745                                                                             -8.36408                                                                            0.566                                                                              -30.3813                                                                            0.604                                                                              -25.7073                                                                            0.483                                                                              -40.5904                                    0.761                                                                               0.701                                                                             -7.88436                                                                            0.341                                                                              -55.1905                                                                            0.201                                                                              -73.5874                                                                            0.111                                                                              -85.4139                                    0.644                                                                               0.418                                                                             -35.0932                                                                            0.289                                                                              -55.1242                                                                            0.125                                                                              -80.5901                                                                            0.103                                                                              -84.0062                                    0.825                                                                               0.549                                                                             -33.4545                                                                            0.266                                                                              -67.7576                                                                            0.133                                                                              -83.8788                                                                            0.049                                                                              -94.0606                                    0.724                                                                               0.624                                                                             -13.8122                                                                            0.432                                                                              -40.3315                                                                            0.313                                                                              -56.768                                                                             0.251                                                                              -65.3315                                    0.679                                                                               0.697                                                                             2.650957                                                                            0.402                                                                              -40.7953                                                                            0.214                                                                              -68.4831                                                                            0.114                                                                              -83.2106                                    0.769                                                                               0.478                                                                             -37.8414                                                                            0.412                                                                              -46.4239                                                                            0.3 -60.9883                                                                            0.137                                                                              -82.1847                                    0.709                                                                               0.48                                                                              -32.299                                                                             0.374                                                                              -47.2496                                                                            0.285                                                                              -59.8025                                                                            0.195                                                                              -72.4965                                    Mean ± S.D.                                                                 0.727                                                                               0.580                                                                             -20.117                                                                             0.378                                                                              -48.014                                                                             0.257                                                                              -65.345                                                                             0.167                                                                              -77.516                                     0.071                                                                               0.116                                                                             14.736                                                                              0.090                                                                              10.711                                                                              0.150                                                                              17.734                                                                              0.134                                                                              16.334                                      __________________________________________________________________________     Day 9   Day 11  Day 14  Day 16  Day 18                                         area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                   __________________________________________________________________________     0.039                                                                             -93.7299                                                                            0.031                                                                             -95.0161                                                                            0  -100 0  -100 0  -100                                        0.288                                                                             -64.5756                                                                            0.104                                                                             -87.2079                                                                            0.039                                                                             -95.203                                                                             0.007                                                                             -99.139                                                                             0  -100                                        0.06                                                                              -92.1156                                                                            0.009                                                                             -98.8173                                                                            0  -100 0  -100 0  -100                                        0.046                                                                             -92.8571                                                                            0  -100 0  -100 0  -100 0  -100                                        0.043                                                                             -94.7879                                                                            0  -100 0  -100 0  -100 0  -100                                        0.173                                                                             -76.105                                                                             0  -100 0  -100 0  -100 0  -100                                        0.084                                                                             -87.6289                                                                            0.104                                                                             -84.6834                                                                            0.13                                                                              -80.8542                                                                            0.046                                                                             -93.2253                                                                            0  -100                                        0.1                                                                               -86.9961                                                                            0.06                                                                              -92.1977                                                                            0  -100 0  -100 0  -100                                        0.196                                                                             -72.3554                                                                            0  -100 0  -100 0  -100 0  -100                                        Mean ± S.D.                                                                 0.114                                                                             -84.572                                                                             0.034                                                                             -95.325                                                                             0.019                                                                             -97.340                                                                             0.006                                                                             -99.152                                                                             0  -100.000                                    0.086                                                                             10.896                                                                              0.044                                                                             6.007                                                                               0.044                                                                             6.382                                                                               0.015                                                                             2.241                                                                               0.000                                                                             0.000                                       __________________________________________________________________________

                                      TABLE 1B                                     __________________________________________________________________________     Wound healing data - Experiment 1                                              Comp B 004-001b: 1 mg/kg, i.v.                                                 __________________________________________________________________________     Day 0                                                                              Day 1    Day 3    Day 5    Day 7                                           area                                                                               area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                   __________________________________________________________________________     0.535                                                                              0.505                                                                              -5.60748                                                                            0.402                                                                              -24.8598                                                                            0.273                                                                              -48.972                                                                             0.162                                                                              -69.7196                                    0.656                                                                              0.611                                                                              -6.85976                                                                            0.194                                                                              -70.4268                                                                            0.083                                                                              -87.3476                                                                            0.017                                                                              -97.4085                                    0.647                                                                              0.631                                                                              -2.47295                                                                            0.365                                                                              -43.5858                                                                            0.3 -53.6321                                                                            0.114                                                                              -82.3802                                    0.813                                                                              0.508                                                                              -37.5154                                                                            0.363                                                                              -55.3506                                                                            0.177                                                                              -78.2288                                                                            0.142                                                                              -82.5338                                    0.781                                                                              0.622                                                                              -20.3585                                                                            0.385                                                                              -50.7042                                                                            0.289                                                                              -62.9962                                                                            0.169                                                                              -78.3611                                    0.785                                                                              0.656                                                                              -16.4331                                                                            0.435                                                                              -44.586                                                                             0.334                                                                              -57.4522                                                                            0.205                                                                              -73.8854                                    0.777                                                                              0.559                                                                              -28.0566                                                                            0.397                                                                              -48.906                                                                             0.361                                                                              -53.5393                                                                            0.259                                                                              -66.6667                                    0.724                                                                              0.618                                                                              -14.6409                                                                            0.528                                                                              -27.0718                                                                            0.455                                                                              -37.1547                                                                            0.323                                                                              -55.3867                                    0.747                                                                              0.756                                                                              1.204819                                                                            0.36                                                                               -51.8072                                                                            0.244                                                                              -67.336                                                                             0.256                                                                              -65.7296                                    0.903                                                                              0.729                                                                              -19.2691                                                                            0.561                                                                              -37.8738                                                                            0.27                                                                               -70.0997                                                                            0.175                                                                              -80.6202                                    Mean ± S.D.                                                                 0.737                                                                              0.620                                                                              -15.001                                                                             0.399                                                                              -45.517                                                                             0.279                                                                              -61.676                                                                             0.182                                                                              -75.269                                     0.103                                                                              0.083                                                                              12.021                                                                              0.100                                                                              13.438                                                                              0.101                                                                              14.717                                                                              0.086                                                                              11.665                                      __________________________________________________________________________     Day 9   Day 11  Day 14  Day 16  Day 18                                         area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                   __________________________________________________________________________     0.109                                                                             79.6262                                                                             0.075                                                                             -85.9813                                                                            0.073                                                                             -86.3551                                                                            0.028                                                                             -94.7664                                                                            0  -100                                        0  -100 0  -100 0  -100 0  -100 0  -100                                        0.057                                                                             -91.1901                                                                            0.054                                                                             -91.6538                                                                            0  -100 0  -100 0  -100                                        0.11                                                                              -86.4699                                                                            0  -100 0  -100 0  -100 0  -100                                        0.069                                                                             -91.1652                                                                            0.046                                                                             -94.1101                                                                            0  -100 0  -100 0  -100                                        0.146                                                                             -81.4013                                                                            0.008                                                                             -98.9809                                                                            0  -100 0  -100 0  -100                                        0.179                                                                             -76.9627                                                                            0.026                                                                             -96.6538                                                                            0  -100 0  -100 0  -100                                        0.235                                                                             -67.5414                                                                            0.017                                                                             -97.6519                                                                            0  -100 0  -100 0  -100                                        0.196                                                                             -73.7617                                                                            0  -100 0  -100 0  -100 0  -100                                        0.077                                                                             -91.4729                                                                            0.049                                                                             -94.5736                                                                            0  -100 0  -100 0  -100                                        Mean ± S.D.                                                                 0.118                                                                             -83.959                                                                             0.028                                                                             -95.961                                                                             0.007                                                                             -98.636                                                                             0.003                                                                             -99.477                                                                             0  -100.000                                    0.072                                                                             9.844                                                                               0.027                                                                             4.533                                                                               0.023                                                                             4.315                                                                               0.009                                                                             1.655                                                                               0.000                                                                             0.000                                       __________________________________________________________________________

                                      TABLE 1C                                     __________________________________________________________________________     Wound healing data - Experiment 1                                              Bentelan 1 mg/kg, i.p.                                                         __________________________________________________________________________     Day 0                                                                              Day 1    Day 3    Day 5    Day 7                                           area                                                                               area                                                                               % variat.                                                                           area                                                                               % variat                                                                            area                                                                               % variat.                                                                           area                                                                               % variat.                                   __________________________________________________________________________     0.671                                                                              0.634                                                                              -5.51416                                                                            0.64                                                                               -4.61997                                                                            0.507                                                                              -24.4411                                                                            0.265                                                                              -60.5067                                    0.76                                                                               0.737                                                                              -3.02632                                                                            0.667                                                                              -12.2368                                                                            0.535                                                                              -29.6053                                                                            0.445                                                                              -41.4474                                    0.703                                                                              0.737                                                                              4.836415                                                                            0.618                                                                              -12.091                                                                             0.277                                                                              -60.5974                                                                            0.246                                                                              -65.0071                                    0.885                                                                              0.898                                                                              1.468927                                                                            0.697                                                                              -21.2429                                                                            0.735                                                                              -16.9492                                                                            0.759                                                                              -14.2373                                    0.788                                                                              0.762                                                                              -3.29949                                                                            0.799                                                                              1.395939                                                                            0.594                                                                              -24.6193                                                                            0.626                                                                              -20.5584                                    0.701                                                                              0.662                                                                              -5.56348                                                                            0.705                                                                              0.570613                                                                            0.493                                                                              -29.6719                                                                            0.46                                                                               -34.3795                                    0.654                                                                              0.631                                                                              -3.51682                                                                            0.666                                                                              1.834862                                                                            0.466                                                                              -28.7462                                                                            0.491                                                                              -24.9235                                    Mean ± S.D.                                                                 0.737                                                                              0.723                                                                              -2.088                                                                              0.685                                                                              -6.627                                                                              0.515                                                                              -30.661                                                                             0.470                                                                              -37.294                                     0.080                                                                              0.094                                                                              3.847                                                                               0.059                                                                              8.820                                                                               0.138                                                                              13.935                                                                              0.183                                                                              19.567                                      __________________________________________________________________________     Day 9   Day 11  Day 14  Day 16  Day 18                                         area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                   __________________________________________________________________________     0.201                                                                             -70.0447                                                                            0.199                                                                             -70.3428                                                                            0.056                                                                             -91.6542                                                                            0.011                                                                             -98.3607                                                                            0  -100                                        0.352                                                                             -53.6842                                                                            0.339                                                                             -55.3947                                                                            0.091                                                                             -88.0263                                                                            0.008                                                                             98.9474                                                                             0  -100                                        0.215                                                                             -69.4168                                                                            0.084                                                                             -88.0512                                                                            0  -100 0  -100 0  -100                                        0.551                                                                             -37.7401                                                                            0.331                                                                             -62.5989                                                                            0.176                                                                             -80.113                                                                             0.031                                                                             -96.4972                                                                            0  -100                                        0.535                                                                             -32.1066                                                                            0.275                                                                             -65.1015                                                                            0  -100 0  -100 0  -100                                        0.302                                                                             -56.9187                                                                            0.162                                                                             -76.8902                                                                            0  -100 0  -100 0  -100                                        0.263                                                                             -59.7859                                                                            0.173                                                                             -73.5474                                                                            0.031                                                                             -95.2599                                                                            0.031                                                                             -95.2599                                                                            0  -100                                        Mean ± S.D.                                                                 0.346                                                                             -54.242                                                                             0.223                                                                             -70.275                                                                             0.051                                                                             -93.579                                                                             0.012                                                                             -98.438                                                                             0.000                                                                             -100.000                                    0.144                                                                             14.609                                                                              0.095                                                                             10.627                                                                              0.065                                                                             7.554                                                                               0.014                                                                             1.891                                                                               0.000                                                                             0.000                                       __________________________________________________________________________

                                      TABLE 1D                                     __________________________________________________________________________     Wound healing data - Experiment 1                                              Saline 10 ml/kg, i.p.                                                          __________________________________________________________________________     Day 0                                                                              Day 1    Day 3    Day 5    Day 7                                           area                                                                               area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                   __________________________________________________________________________     0.937                                                                              0.929                                                                              -0.854                                                                              0.636                                                                              -32.1238                                                                            0.398                                                                              -57.524                                                                             0.275                                                                              -70.651                                     0.997                                                                              0.948                                                                              -4.915                                                                              0.675                                                                              -32.2969                                                                            0.601                                                                              -39.7192                                                                            0.463                                                                              -53.5607                                    0.833                                                                              0.856                                                                              2.761                                                                               0.854                                                                              2.521008                                                                            0.793                                                                              -4.80192                                                                            0.749                                                                              -10.084                                     0.804                                                                              0.796                                                                              -0.995                                                                              0.797                                                                              -0.87065                                                                            0.767                                                                              -4.60199                                                                            0.751                                                                              -6.59204                                    0.697                                                                              0.825                                                                              18.364                                                                              0.605                                                                              -13.1994                                                                            0.644                                                                              -7.60402                                                                            0.64                                                                               -8.17791                                    0.729                                                                              0.745                                                                              2.195                                                                               0.626                                                                              -14.1289                                                                            0.454                                                                              -37.7229                                                                            0.385                                                                              -47.1879                                    0.618                                                                              0.645                                                                              4.369                                                                               0.518                                                                              -16.1812                                                                            0.327                                                                              -47.0874                                                                            0.209                                                                              -66.1812                                    0.72                                                                               0.594                                                                              -17.500                                                                             0.528                                                                              -26.6667                                                                            0.287                                                                              -60.1389                                                                            0.189                                                                              -73.75                                      Mean ± S.D.                                                                 0.792                                                                              0.792                                                                              0.428                                                                               0.655                                                                              -16.618                                                                             0.534                                                                              -32.400                                                                             0.458                                                                              -42.023                                     0.127                                                                              0.126                                                                              9.996                                                                               0.119                                                                              13.199                                                                              0.195                                                                              23.444                                                                              0.232                                                                              29.254                                      __________________________________________________________________________     Day 9   Day 11  Day 14  Day 16  Day 18                                         area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                   __________________________________________________________________________     0.127                                                                             -86.4461                                                                            0.139                                                                             -85.1654                                                                            0  -100 0  -100 0  -100                                        0.366                                                                             -63.2899                                                                            0.297                                                                             -70.2106                                                                            0.039                                                                             -96.0883                                                                            0  -100 0  -100                                        0.608                                                                             -27.0108                                                                            0.339                                                                             -59.3037                                                                            0.151                                                                             -81.8727                                                                            0.02                                                                              -97.599                                                                             0  -100                                        0.541                                                                             -32.7114                                                                            0.36                                                                              -55.2239                                                                            0.1                                                                               -87.5622                                                                            0  -100 0  -100                                        0.512                                                                             -26.5423                                                                            0.347                                                                             -50.2152                                                                            0.128                                                                             -81.6356                                                                            0.026                                                                             -96.2697                                                                            0  -100                                        0.331                                                                             -54.5953                                                                            0.238                                                                             -67.3525                                                                            0.012                                                                             -98.3539                                                                            0  -100 0  -100                                        0.132                                                                             -78.6408                                                                            0  -100 0  -100 0  -100 0  -100                                        0.085                                                                             -88.1944                                                                            0  -100 0  -100 0  -100 0  -100                                        Mean ± S.D.                                                                 0.338                                                                             -57.179                                                                             0.215                                                                             -73.434                                                                             0.054                                                                             -93.189                                                                             0.006                                                                             -99.234                                                                             0.000                                                                             -100.000                                    0.206                                                                             26.106                                                                              0.151                                                                             19.519                                                                              0.063                                                                             8.172                                                                               0.011                                                                             1.463                                                                               0.000                                                                             0.000                                       __________________________________________________________________________

                                      TABLE 2A                                     __________________________________________________________________________     Wound healing data - Experiment 2                                              Comp B 004-001b: 0.1 mg/kg, i.v.                                               __________________________________________________________________________     Day 0                                                                              Day 1   Day 3    Day 5   Day 7                                             area                                                                               area                                                                              % variat.                                                                           area                                                                               % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                      __________________________________________________________________________     0.679                                                                              0.58                                                                              -14.5803                                                                            0.561                                                                              -17.3785                                                                            0.566                                                                             -16.6421                                                                            0.347                                                                             -48.8954                                       0.693                                                                              0.677                                                                             -2.3088                                                                             0.635                                                                              -8.36941                                                                            0.603                                                                             -12.987                                                                             0.493                                                                             -28.86                                         1.002                                                                              0.759                                                                             -24.2515                                                                            0.84                                                                               -16.1677                                                                            0.749                                                                             -25.2495                                                                            0.525                                                                             -47.6048                                       0.833                                                                              0.677                                                                             -18.7275                                                                            0.701                                                                              -15.8463                                                                            0.584                                                                             -29.892                                                                             0.401                                                                             -51.8607                                       0.671                                                                              0.597                                                                             -11.0283                                                                            0.458                                                                              -31.7437                                                                            0.412                                                                             -38.5991                                                                            0.282                                                                             -57.9732                                       0.651                                                                              0.526                                                                             -19.2012                                                                            0.604                                                                              -7.21966                                                                            0.556                                                                             -14.5929                                                                            0.424                                                                             -34.8694                                       0.682                                                                              0.755                                                                             10.70381                                                                            0.452                                                                              -33.7243                                                                            0.512                                                                             -24.9267                                                                            0.242                                                                             -64.5161                                       0.817                                                                              0.601                                                                             -26.4382                                                                            0.55                                                                               -32.6805                                                                            0.486                                                                             -40.5141                                                                            0.408                                                                             -50.0612                                       0.693                                                                              0.538                                                                             -22.3665                                                                            0.418                                                                              -39.6825                                                                            0.307                                                                             -55.6999                                                                            0.246                                                                             -64.5022                                       0.799                                                                              0.58                                                                              -27.4093                                                                            0.58                                                                               -27.4093                                                                            0.461                                                                             -42.3029                                                                            0.418                                                                             -47.6846                                       0.777                                                                              0.686                                                                             -11.7117                                                                            0.563                                                                              -27.5418                                                                            0.433                                                                             -44.2728                                                                            0.282                                                                             -63.7066                                       Mean ± S.D.                                                                 0.754                                                                              0.634                                                                             -15.211                                                                             0.578                                                                              -23.433                                                                             0.515                                                                             -31.425                                                                             0.379                                                                             -49.683                                        0.105                                                                              0.081                                                                             11.420                                                                              0.120                                                                              10.927                                                                              0.117                                                                             13.897                                                                              0.098                                                                             11.427                                         __________________________________________________________________________     Day 9   Day 11   Day 14     Day 16                                             area                                                                              % variat.                                                                           area                                                                               % variat.                                                                           area  % variat.                                                                           area                                                                               % variat.                                      __________________________________________________________________________     0.347                                                                             -48.8954                                                                            0.196                                                                              -71.134                                                                             0.009 -98.6745                                                                            0   -100                                           0.309                                                                             -55.4113                                                                            0.139                                                                              -79.9423                                                                            0.039 -94.3723                                                                            0.012                                                                              -98.27                                         0.454                                                                             -54.6906                                                                            0.146                                                                              -85.4291                                                                            0.058 -94.2116                                                                            0.018                                                                              -98.20                                         0.206                                                                             -75.2701                                                                            0.053                                                                              -93.6375                                                                            0     -100 0   -100                                           0.238                                                                             -64.5306                                                                            0.142                                                                              -78.8376                                                                            0.04  -94.0387                                                                            0   -100                                           0.329                                                                             -49.4624                                                                            0.216                                                                              -66.8203                                                                            0.15  -76.9585                                                                            0.052                                                                              -92.01                                         0.179                                                                             -73.7537                                                                            0.046                                                                              -93.2551                                                                            0     -100 0   -100                                           0.282                                                                             -65.4835                                                                            0.177                                                                              -78.3354                                                                            0     -100 0   -100                                           0.231                                                                             -66.6667                                                                            0.122                                                                              -82.3954                                                                            0     -100 0   -100                                           0.409                                                                             -48.811                                                                             0.203                                                                              -74.5932                                                                            0     -100 0   -100                                           0.225                                                                             -71.0425                                                                            0.105                                                                              -86.4865                                                                            0.008 -98.9704                                                                            0   -100                                           Mean ± S.D.                                                                 0.292                                                                             -61.274                                                                             0.140                                                                              -80.988                                                                             0.027636                                                                             -96.111                                                                             0.007                                                                              -98.953                                        0.087                                                                             10.150                                                                              0.057                                                                              8.449                                                                               0.046 6.842                                                                               0.016                                                                              2.408                                          __________________________________________________________________________     Day 18      Day 21       Day 23                                                area % variat.                                                                             area % variat.                                                                              area % variat.                                        __________________________________________________________________________     0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             0    -100   0    -100    0    -100                                             Mean ± S.D.                                                                 0.000                                                                               -100.000                                                                              0    -100.000                                                                               0    -100.000                                         0.000                                                                               0.000  0.000                                                                               0.000   0.000                                                                               0.000                                            __________________________________________________________________________

                                      TABLE 2B                                     __________________________________________________________________________     Wound healing data - Experiment 2                                              Comp B 004-001b: 1 mg/kg, i.v.                                                 __________________________________________________________________________     Day 0                                                                              Day 1    Day 3   Day 5   Day 7                                             area                                                                               area                                                                               % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                      __________________________________________________________________________     0.769                                                                              0.601                                                                              -21.8466                                                                            0.455                                                                             -40.8322                                                                            0.297                                                                             -61.3784                                                                            0.121                                                                             -84.2653                                       0.763                                                                              0.525                                                                              -31.1927                                                                            0.493                                                                             -35.3866                                                                            0.464                                                                             -39.1874                                                                            0.451                                                                             -40.8912                                       0.964                                                                              0.712                                                                              -26.1411                                                                            0.358                                                                             -62.8631                                                                            0.287                                                                             -70.2282                                                                            0.134                                                                             -86.0996                                       0.712                                                                              0.573                                                                              -19.5225                                                                            0.421                                                                             -40.8708                                                                            0.563                                                                             -20.927                                                                             0.179                                                                             -74.8596                                       0.763                                                                              0.59                                                                               -22.6737                                                                            0.266                                                                             -65.1376                                                                            0.155                                                                             -79.6855                                                                            0.054                                                                             -92.9227                                       0.793                                                                              0.747                                                                              -5.80076                                                                            0.415                                                                             -47.6671                                                                            0.334                                                                             -57.8815                                                                            0.185                                                                             -76.6709                                       0.785                                                                              0.451                                                                              -42.5478                                                                            0.238                                                                             -69.6815                                                                            0.199                                                                             -74.6497                                                                            0.168                                                                             -78.5987                                       0.747                                                                              0.701                                                                              -6.15797                                                                            0.458                                                                             -38.6881                                                                            0.398                                                                             -46.7202                                                                            0.29                                                                              -61.178                                        0.873                                                                              0.765                                                                              -12.3711                                                                            0.73                                                                              -16.3803                                                                            0.667                                                                             -23.5968                                                                            0.515                                                                             -41.008                                        0.979                                                                              0.867                                                                              -11.4402                                                                            0.667                                                                             -31.8693                                                                            0.594                                                                             -39.3258                                                                            0.448                                                                             -54.239                                        0.833                                                                              0.716                                                                              -14.0456                                                                            0.594                                                                             -28.6915                                                                            0.528                                                                             -36.6146                                                                            0.395                                                                             -52.581                                        1.225                                                                              0.72                                                                               -41.2245                                                                            0.528                                                                             -56.898                                                                             0.458                                                                             -62.6122                                                                            0.384                                                                             -68.6531                                       Mean ± S.D.                                                                 0.8505                                                                             0.664                                                                              -21.247                                                                             0.469                                                                             -44.581                                                                             0.412                                                                             -51.067                                                                             0.277                                                                             -67.664                                        0.145                                                                              0.117                                                                              12.337                                                                              0.148                                                                             16.249                                                                              0.161                                                                             19.536                                                                              0.156                                                                             17.540                                         __________________________________________________________________________     Day 9    Day 11   Day 14   Day 16                                              area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                       __________________________________________________________________________     0.056                                                                              -92.7178                                                                            0.044                                                                              -94.2783                                                                            0   -100 0   -100                                            0.344                                                                              -54.9148                                                                            0.146                                                                              -80.865                                                                             0   -100 0   -100                                            0.03                                                                               -96.888                                                                             0   -100 0   -100 0   -100                                            0.171                                                                              -75.9831                                                                            0.021                                                                              -97.0506                                                                            0   -100 0   -100                                            0.038                                                                              -95.0197                                                                            0   -100 0   -100 0   -100                                            0.061                                                                              -92.3077                                                                            0.024                                                                              -96.9735                                                                            0   -100 0   -100                                            0.039                                                                              -95.0318                                                                            0   -100 0   -100 0   -100                                            0.138                                                                              -81.5261                                                                            0.038                                                                              -94.913                                                                             0   -100 0   -100                                            0.344                                                                              -60.5956                                                                            0.192                                                                              -78.0069                                                                            0   -100 0   -100                                            0.186                                                                              -81.001                                                                             0.019                                                                              -98.0592                                                                            0   -100 0   -100                                            0.238                                                                              -71.4286                                                                            0.159                                                                              -80.9124                                                                            0   -100 0   -100                                            0.392                                                                              -68  0.148                                                                              -87.9184                                                                            0   -100 0   -100                                            Mean ± S.D.                                                                 0.170                                                                              -80.451                                                                             0.066                                                                              -92.415                                                                             0   -100.000                                                                            0   -100.000                                        0.133                                                                              14.429                                                                              0.073                                                                              8.257                                                                               0.000                                                                              0.000                                                                               0.000                                                                              0.000                                           __________________________________________________________________________

                                      TABLE 2C                                     __________________________________________________________________________     Wound healing data - Experiment 2                                              Bentelan 1 mg/kg, i.v.                                                         __________________________________________________________________________     Day 0                                                                              Day 1   Day 3    Day 5   Day 7                                             area                                                                               area                                                                              % variat.                                                                           area                                                                               % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                      __________________________________________________________________________     0.789                                                                              0.813                                                                             3.041825                                                                            0.767                                                                              -2.78834                                                                            0.615                                                                             -22.0532                                                                            0.565                                                                             -28.3904                                       0.769                                                                              0.831                                                                             8.062419                                                                            0.846                                                                              10.013                                                                              0.833                                                                             8.322497                                                                            0.751                                                                             -2.3407                                        0.805                                                                              0.741                                                                             -7.95031                                                                            0.751                                                                              -6.70807                                                                            0.763                                                                             -5.21739                                                                            0.525                                                                             -34.7826                                       0.751                                                                              0.86                                                                              14.51398                                                                            0.825                                                                              9.853529                                                                            0.997                                                                             32.75632                                                                            0.586                                                                             -21.9707                                       0.842                                                                              0.864                                                                             2.612827                                                                            0.858                                                                              1.900238                                                                            0.773                                                                             -8.19477                                                                            0.675                                                                             -19.8337                                       0.856                                                                              0.739                                                                             -13.6682                                                                            0.769                                                                              -10.1636                                                                            0.712                                                                             -16.8224                                                                            0.636                                                                             -25.7009                                       0.651                                                                              0.679                                                                             4.301075                                                                            0.69                                                                               5.990783                                                                            0.626                                                                             -3.84025                                                                            0.555                                                                             -14.7465                                       0.769                                                                              0.679                                                                             -11.7035                                                                            0.636                                                                              -17.2952                                                                            0.656                                                                             -14.6944                                                                            0.622                                                                             -19.1157                                       0.763                                                                              0.86                                                                              12.71298                                                                            0.869                                                                              13.89253                                                                            0.777                                                                             1.834862                                                                            0.751                                                                             -1.57274                                       0.675                                                                              0.679                                                                             0.592593                                                                            0.769                                                                              13.92593                                                                            0.709                                                                             5.037037                                                                            0.655                                                                             -2.96296                                       0.805                                                                              0.667                                                                             -17.1429                                                                            0.69                                                                               -14.2857                                                                            0.72                                                                              -10.559                                                                             0.622                                                                             -22.7329                                       0.644                                                                              0.886                                                                             37.57764                                                                            0.809                                                                              25.62112                                                                            0.565                                                                             -12.2671                                                                            0.551                                                                             -14.441                                        Mean ± S.D.                                                                 0.760                                                                              0.775                                                                             2.746                                                                               0.773                                                                              2.496                                                                               0.729                                                                             -3.808                                                                              0.625                                                                             -17.383                                        0.070                                                                              0.086                                                                             14.999                                                                              0.073                                                                              13.020                                                                              0.115                                                                             14.627                                                                              0.074                                                                             10.667                                         __________________________________________________________________________     Day 9    Day 11   Day 14   Day 16                                              area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                       __________________________________________________________________________     0.317                                                                              -59.8226                                                                            0.258                                                                              -67.3004                                                                            0.151                                                                              -80.8619                                                                            0.081                                                                              -89.7338                                        0.424                                                                              -44.8635                                                                            0.344                                                                              -55.2666                                                                            0.222                                                                              -71.1313                                                                            0.11                                                                               -85.6957                                        0.457                                                                              -43.2298                                                                            0.312                                                                              -61.2422                                                                            0.181                                                                              -77.5155                                                                            0.066                                                                              -91.8012                                        0.755                                                                              0.532623                                                                            0.587                                                                              -21.8375                                                                            0.369                                                                              -50.8655                                                                            0.216                                                                              -71.2383                                        0.545                                                                              -35.2732                                                                            0.315                                                                              -62.5891                                                                            0.117                                                                              -86.1045                                                                            0.026                                                                              -96.9121                                        0.43                                                                               -49.7664                                                                            0.259                                                                              -69.743                                                                             0.118                                                                              -86.215                                                                             0.035                                                                              -95.9112                                        0.396                                                                              -39.1705                                                                            0.24                                                                               -63.1336                                                                            0.071                                                                              -89.0937                                                                            0   -100                                            0.433                                                                              -43.6931                                                                            0.309                                                                              -59.8179                                                                            0.212                                                                              -72.4317                                                                            0.025                                                                              -96.749                                         0.594                                                                              -22.1494                                                                            0.433                                                                              -43.2503                                                                            0.092                                                                              -87.9423                                                                            0.016                                                                              -97.903                                         0.415                                                                              -38.5185                                                                            0.325                                                                              -51.8519                                                                            0.203                                                                              -69.9259                                                                            0.036                                                                              -94.6667                                        0.499                                                                              -38.0124                                                                            0.302                                                                              -62.4845                                                                            0.157                                                                              -80.4969                                                                            0.013                                                                              -98.3851                                        0.312                                                                              -51.5528                                                                            0.124                                                                              -80.7453                                                                            0.033                                                                              -94.8758                                                                            0   -100                                            Mean ± S.D.                                                                 0.465                                                                              -38.793                                                                             0.317                                                                              -58.272                                                                             0.161                                                                              -78.955                                                                             0.052                                                                              -93.250                                         0.122                                                                              15.500                                                                              0.112                                                                              14.749                                                                              0.0881                                                                             11.768                                                                              0.061                                                                              8.146                                           __________________________________________________________________________     Day 18       Day 21      Day 23                                                area % variat.                                                                              area % variat.                                                                             area % variat.                                        __________________________________________________________________________     0.02 -97.4651                                                                               0    -100   0    -100                                             0.059                                                                               -92.3277                                                                               0.047                                                                               -99417 0    -100                                             0.01 -98.7578                                                                               0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0.015                                                                               -98.0494                                                                               0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             Mean ± S.D.                                                                 0.009                                                                               -98.883 0.004                                                                               -99.951                                                                               0.000                                                                               -100.000                                         0.017                                                                               2.250   0.014                                                                               0.168  0.000                                                                               0.000                                            __________________________________________________________________________

                                      TABLE 2D                                     __________________________________________________________________________     Wound healing data - Experiment 2                                              Saline 10 ml/kg, i.v.                                                          __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7                                              area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                       __________________________________________________________________________     0.58                                                                               0.594                                                                             2.413793                                                                            0.535                                                                             -7.75862                                                                            0.538                                                                             -7.24138                                                                            0.466                                                                             -19.6552                                        0.773                                                                              0.755                                                                             -2.32859                                                                            0.763                                                                             -1.29366                                                                            0.584                                                                             -24.4502                                                                            0.561                                                                             -27.4256                                        0.735                                                                              0.785                                                                             6.802721                                                                            0.779                                                                             5.986395                                                                            0.735                                                                             0    0.622                                                                             -15.3741                                        0.805                                                                              0.666                                                                             -17.2671                                                                            0.655                                                                             -18.6335                                                                            0.615                                                                             -23.6025                                                                            0.385                                                                             -52.1739                                        0.701                                                                              0.629                                                                             -10.271                                                                             0.629                                                                             -10.271                                                                             0.546                                                                             -22.1113                                                                            0.493                                                                             -29.6719                                        0.686                                                                              0.671                                                                             -2.18659                                                                            0.584                                                                             -14.8688                                                                            0.535                                                                             -22.0117                                                                            0.478                                                                             -30.3207                                        0.601                                                                              0.59                                                                              -1.83028                                                                            0.58                                                                              -3.49418                                                                            0.536                                                                             -10.8153                                                                            0.451                                                                             -24.9584                                        0.759                                                                              0.747                                                                             -1.58103                                                                            0.72                                                                              -5.13834                                                                            0.627                                                                             -17.3913                                                                            0.551                                                                             -27.4045                                        Mean ± S.D.                                                                 0.705                                                                              0.680                                                                             -3.281                                                                              0.656                                                                             -6.934                                                                              0.590                                                                             -15.953                                                                             0.501                                                                             -28.373                                         0.080                                                                              0.075                                                                             7.423                                                                               0.090                                                                             7.796                                                                               0.069                                                                             8.978                                                                               0.074                                                                             10.892                                          Day 9    Day 11   Day 14    Day 16                                             area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area % variat.                                                                           area                                                                               % variat.                                      __________________________________________________________________________     0.325                                                                              -43.9655                                                                            0.206                                                                              -64.4828                                                                            0.206                                                                               -64.4828                                                                            0.104                                                                              -82.069                                        0.339                                                                              -56.1449                                                                            0.238                                                                              -69.2109                                                                            0.181                                                                               -76.5847                                                                            0.116                                                                              -84.9935                                       0.436                                                                              -40.6803                                                                            0.187                                                                              -74.5578                                                                            0.197                                                                               -73.1973                                                                            0.067                                                                              -90.8844                                       0.408                                                                              -49.3168                                                                            0.28                                                                               -65.2174                                                                            0.216                                                                               -73.1677                                                                            0.047                                                                              -94.1615                                       0.369                                                                              -47.3609                                                                            0.249                                                                              -64.4793                                                                            0.238                                                                               -66.0485                                                                            0.036                                                                              -94.8645                                       0.246                                                                              -64.1399                                                                            0.273                                                                              -60.2041                                                                            0.175                                                                               -74.4898                                                                            0   -100                                           0.282                                                                              -53.0782                                                                            0.297                                                                              -50.5824                                                                            0.201                                                                               -66.5557                                                                            0.048                                                                              -92.0133                                       0.469                                                                              -38.2082                                                                            0.377                                                                              -50.3294                                                                            0.24 -68.3794                                                                            0.036                                                                              -95.2569                                       Mean ± S.D.                                                                 0.359                                                                              -49.112                                                                             0.263                                                                              -62.383                                                                             0.20675                                                                             -70.363                                                                             0.057                                                                              -91.780                                        0.076                                                                              8.541                                                                               0.059                                                                              8.460                                                                               0.024                                                                               4.524                                                                               0.038                                                                              5.807                                          __________________________________________________________________________     Day 18       Day 21      Day 23                                                area % variat.                                                                              area % variat.                                                                             area % variat.                                        __________________________________________________________________________     0.027                                                                               95.3448 0    -100   0    -100                                             0.041                                                                               -94.696 0.027                                                                               -96.5071                                                                              0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0.017                                                                               -97.7602                                                                               0    -100   0    -100                                             Mean ± S.D.                                                                 0.011                                                                               -98.475 0.003                                                                               -99.563                                                                               0.000                                                                               -100.000                                         0.016                                                                               2.275   0.010                                                                               1.235  0.000                                                                               0.000                                            __________________________________________________________________________

                                      TABLE 3A                                     __________________________________________________________________________     Wound healing data - Experiment 3                                              Component B (004-001) 1 μg                                                  __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7                                              area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                               % variat.                                      __________________________________________________________________________     0.746                                                                              0.709                                                                             -4.95979                                                                            0.584                                                                             -21.7158                                                                            0.477                                                                             -36.059                                                                             0.305                                                                              -59.1153                                       0.92                                                                               0.659                                                                             -28.3696                                                                            0.404                                                                             -56.087                                                                             0.304                                                                             -66.9565                                                                            0.242                                                                              -73.6957                                       0.687                                                                              0.618                                                                             -10.0437                                                                            0.466                                                                             -32.1689                                                                            0.444                                                                             -35.3712                                                                            0.41                                                                               -40.3202                                       0.818                                                                              0.822                                                                             0.488998                                                                            0.503                                                                             -38.5086                                                                            0.388                                                                             -52.5672                                                                            0.372                                                                              -54.5232                                       0.742                                                                              0.571                                                                             -23.0458                                                                            0.451                                                                             -39.2183                                                                            0.399                                                                             -46.2264                                                                            0.372                                                                              -49.8652                                       0.716                                                                              0.677                                                                             -5.44693                                                                            0.636                                                                             -I1.1732                                                                            0.548                                                                             -23.4637                                                                            0.503                                                                              -29.7486                                       0.833                                                                              0.638                                                                             -23.4094                                                                            0.487                                                                             -41.5366                                                                            0.402                                                                             -51.7407                                                                            0.377                                                                              -54.7419                                       0.659                                                                              0.52                                                                              -21.0926                                                                            0.49                                                                              -25.6449                                                                            0.425                                                                             -35.5083                                                                            0.332                                                                              -49.6206                                       0.738                                                                              0.724                                                                             -1.89702                                                                            0.571                                                                             -22.6287                                                                            0.491                                                                             -33.4688                                                                            0.466                                                                              -36.8564                                       0.705                                                                              0.545                                                                             -22.695                                                                             0.233                                                                             -66.9504                                                                            0.195                                                                             -72.3404                                                                            0.152                                                                              -78.4397                                       Mean ± S.D.                                                                 0.756                                                                              0.648                                                                             -14.047                                                                             0.471                                                                             -35.563                                                                             0.407                                                                             -45.370                                                                             0.353                                                                              -52.693                                        0.079                                                                              0.091                                                                             10.696                                                                              0.112                                                                             16.759                                                                              0.100                                                                             15.606                                                                              0.103                                                                              15.277                                         __________________________________________________________________________     Day 9    Day 11   Day 14   Day 16                                              area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                       __________________________________________________________________________     0.41                                                                               -45.0402                                                                            0.129                                                                              -82.7078                                                                            0.056                                                                              -92.4933                                                                            0   -100                                            0.181                                                                              -80.3261                                                                            0.09                                                                               -90.2174                                                                            0.008                                                                              -99.1304                                                                            0   -100                                            0.366                                                                              -46.7249                                                                            0.15                                                                               -78.1659                                                                            0.099                                                                              -85.5895                                                                            0   -100                                            0.345                                                                              -57.824                                                                             0.198                                                                              -75.7946                                                                            0.063                                                                              -92.2983                                                                            0.033                                                                              -95.9658                                        0.271                                                                              -63.4771                                                                            0.12                                                                               -83.8275                                                                            0   -100 0   -100                                            0.475                                                                              -33.6592                                                                            0.267                                                                              -62.7095                                                                            0.02                                                                               -97.2067                                                                            0   -100                                            0.35                                                                               -57.9832                                                                            0.204                                                                              -75.5102                                                                            0.045                                                                              -94.5978                                                                            0   -100                                            0.246                                                                              -62.6707                                                                            0.11                                                                               -83.308                                                                             0.017                                                                              -97.4203                                                                            0   -100                                            0.401                                                                              -45.664                                                                             0.18                                                                               -75.6098                                                                            0.031                                                                              -95.7995                                                                            0.008                                                                              -98.916                                         0.11                                                                               -84.3972                                                                            0.189                                                                              -73.1915                                                                            0.008                                                                              -98.8652                                                                            0.008                                                                              -98.8652                                        Mean ± S.D.                                                                 0.316                                                                              -57.777                                                                             0.164                                                                              -78.104                                                                             0.035                                                                              -95.340                                                                             0.005                                                                              -99.375                                         0.112                                                                              15.939                                                                              0.054                                                                              7.507                                                                               0.031                                                                              4.340                                                                               0.010                                                                              1.284                                           __________________________________________________________________________     Day 18       Day 21      Day 23                                                area % variat.                                                                              area % variat.                                                                             area % variat.                                        __________________________________________________________________________     0    100     0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             Mean ± S.D.                                                                 0    -100.000                                                                               0    -100   0    -100                                             0.000                                                                               0.000   0.000                                                                               0.000  0.000                                                                               0.000                                            __________________________________________________________________________

                                      TABLE 3B                                     __________________________________________________________________________     Wound healing data - Experiment 3                                              Phosphate buffer                                                               __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7                                              area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                       __________________________________________________________________________     0.785                                                                              0.75                                                                              -4.4586                                                                             0.747                                                                             -4.84076                                                                            0.285                                                                             -63.6943                                                                            0.271                                                                             -65.4777                                        0.673                                                                              0.768                                                                             14.1159                                                                             0.731                                                                             8.618128                                                                            0.626                                                                             -6.98366                                                                            0.612                                                                             -9.06389                                        0.785                                                                              0.772                                                                             14.71025                                                                            0.747                                                                             -4.84076                                                                            0.487                                                                             -37.9618                                                                            0.439                                                                             -44.0764                                        0.902                                                                              0.902                                                                             0    0.862                                                                             -4.43459                                                                            0.754                                                                             -16.408                                                                             0.739                                                                             -18.071                                         0.785                                                                              0.742                                                                             -5.47771                                                                            0.766                                                                             -2.42038                                                                            0.535                                                                             -31.8471                                                                            0.531                                                                             -32.3567                                        0.694                                                                              0.694                                                                             0    0.672                                                                             -3.17003                                                                            0.448                                                                             -35.4467                                                                            0.433                                                                             -37.6081                                        0.733                                                                              0.846                                                                             15.4161                                                                             0.743                                                                             1.364256                                                                            0.506                                                                             -30.9686                                                                            0.487                                                                             -33.5607                                        0.666                                                                              0.742                                                                             11.41141                                                                            0.778                                                                             16.81682                                                                            0.535                                                                             -19.6697                                                                            0.475                                                                             -28.6787                                        0.768                                                                              0.765                                                                             -0.39063                                                                            0.687                                                                             -10.5469                                                                            0.312                                                                             -59.375                                                                             0.322                                                                             -58.0729                                        Mean ± S.D.                                                                 0.755                                                                              0.776                                                                             5.036                                                                               0.748                                                                             -0.384                                                                              0.499                                                                             -33.595                                                                             0.479                                                                             -36.330                                         0.074                                                                              0.062                                                                             8.698                                                                               0.055                                                                             8.301                                                                               0.145                                                                             18.710                                                                              0.141                                                                             17.828                                          __________________________________________________________________________     Day 9     Day 11   Day 14   Day 16                                             area % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                              % variat.                                       __________________________________________________________________________     0.26 66.879                                                                              0.221                                                                              -71.8471                                                                            0.107                                                                              -86.3694                                                                            0.042                                                                             -94.6497                                        0.522                                                                               -22.4368                                                                            0.217                                                                              -67.7563                                                                            0.057                                                                              -91.5305                                                                            0  -100                                            0.401                                                                               -48.9172                                                                            0.374                                                                              -52.3567                                                                            0.15                                                                               -80.8917                                                                            0.096                                                                             -87.7707                                        0.601                                                                               -33.3703                                                                            0.324                                                                              -64.0798                                                                            0.103                                                                              -88.5809                                                                            0.038                                                                             -95.7871                                        0.535                                                                               -31.8471                                                                            0.358                                                                              -54.3949                                                                            0.15                                                                               -80.8917                                                                            0.04                                                                              -94.9045                                        0.382                                                                               -44.9568                                                                            0.238                                                                              -65.7061                                                                            0.128                                                                              -81.5562                                                                            0.053                                                                             -92.3631                                        0.46 -37.2442                                                                            0.3 -59.0723                                                                            0.1 -86.3574                                                                            0.058                                                                             -92.0873                                        0.255                                                                               -61.7117                                                                            0.264                                                                              -60.3604                                                                            0.101                                                                              -84.8348                                                                            0.102                                                                             -84.6847                                        0.297                                                                               -61.3281                                                                            0.269                                                                              -64.974                                                                             0.025                                                                              -96.7448                                                                            0  -100                                            Mean ± S.D.                                                                 0.413                                                                               -45.410                                                                             0.285                                                                              -62.283                                                                             0.102                                                                              -86.418                                                                             0.048                                                                             -93.583                                         47.474                                                                              15.475                                                                              0.058                                                                              6.308                                                                               0.041                                                                              5.300                                                                               0.036                                                                             5.084                                           __________________________________________________________________________     Day 18       Day 21      Day 23                                                area % variat.                                                                              area % variat.                                                                             area % variat.                                        __________________________________________________________________________     0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0.008                                                                               -99.1131                                                                               0    -100   0    -100                                             0.012                                                                               -98.4713                                                                               0.012                                                                               -98.4713                                                                              0    -100                                             0.041                                                                               -94.0922                                                                               0.008                                                                               -98.8473                                                                              0    -100                                             0.008                                                                               -98.9086                                                                               0    -100   0    -100                                             0.092                                                                               -86.1862                                                                               0.095                                                                               -85.7357                                                                              0    -100                                             0    -100    0    -100   0    -100                                             Mean ± S.D.                                                                 0.018                                                                               -97.419 0.013                                                                               -98.117                                                                               0.000                                                                               -100.000                                         0.031                                                                               4.611   0.031                                                                               4.680  0.000                                                                               0.000                                            __________________________________________________________________________

                                      TABLE 3C                                     __________________________________________________________________________     Wound healing data - Experiment 3                                              Component B (004-001) 4 μg                                                  __________________________________________________________________________     Day 0                                                                              Day 1   Day 3    Day 5   Day 7                                             area                                                                               area                                                                              % variat.                                                                           area                                                                               % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                      __________________________________________________________________________     0.826                                                                              0.604                                                                             -26.8765                                                                            0.512                                                                              -38.0145                                                                            0.293                                                                             -64.5278                                                                            0.248                                                                             -69.9758                                       0.731                                                                              0.635                                                                             -13.1327                                                                            0.515                                                                              -29.5486                                                                            0.371                                                                             -49.2476                                                                            0.324                                                                             -55.6772                                       0.785                                                                              0.659                                                                             -16.051                                                                             0.538                                                                              -31.465                                                                             0.43                                                                              -45.2229                                                                            0.358                                                                             -54.3949                                       0.803                                                                              0.742                                                                             -7.59651                                                                            0.601                                                                              -25.1557                                                                            0.49                                                                              -38.9788                                                                            0.427                                                                             -46.8244                                       0.727                                                                              0.691                                                                             -4.95186                                                                            0.676                                                                              -7.01513                                                                            0.509                                                                             -29.9862                                                                            0.468                                                                             -35.6259                                       0.785                                                                              0.581                                                                             -25.9873                                                                            0.506                                                                              -35.5414                                                                            0.379                                                                             -51.7197                                                                            0.278                                                                             -64.586                                        0.866                                                                              0.523                                                                             -39.6074                                                                            0.329                                                                              -62.0092                                                                            0.218                                                                             -74.8268                                                                            0.161                                                                             -81.4088                                       0.757                                                                              0.666                                                                             -12.0211                                                                            0.582                                                                              -23.1176                                                                            0.407                                                                             -46.2351                                                                            0.319                                                                             -57.86                                         0.799                                                                              0.526                                                                             -34.1677                                                                            0.319                                                                              -60.0751                                                                            0.236                                                                             -70.4631                                                                            0.169                                                                             -78.8486                                       0.81                                                                               0.568                                                                             -29.8765                                                                            0.430                                                                              -46.9136                                                                            0.374                                                                             -53.8272                                                                            0.292                                                                             -63.9506                                       Mean ± S.D.                                                                 0.789                                                                              0.620                                                                             -21.027                                                                             0.501                                                                              -35.886                                                                             0.371                                                                             -52.504                                                                             0.304                                                                             -60.915                                        0.043                                                                              0.072                                                                             11.842                                                                              0.114                                                                              16.883                                                                              0.098                                                                             13.987                                                                              0.099                                                                             13.999                                         __________________________________________________________________________     Day 9    Day 11   Day 14   Day 16                                              area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                                                           area                                                                               % variat.                                       __________________________________________________________________________     0.187                                                                              -77.3608                                                                            0.106                                                                              -87.1671                                                                            0.02                                                                               -97.5787                                                                            0   -100                                            0.208                                                                              -71.5458                                                                            0.132                                                                              -81.9425                                                                            0   -100 0   -100                                            0.223                                                                              -71.5924                                                                            0.102                                                                              -87.0064                                                                            0   -100 0   -100                                            0.283                                                                              -64.7572                                                                            0.126                                                                              -84.3088                                                                            0.01                                                                               -98.7547                                                                            0   -100                                            0.311                                                                              -57.2215                                                                            0.145                                                                              -80.055                                                                             0   -100 0   -100                                            0.188                                                                              -76.051                                                                             0.008                                                                              -98.9809                                                                            0   -100 0   -100                                            0.138                                                                              -84.0647                                                                            0.008                                                                              -99.0762                                                                            0   -100 0   -100                                            0.264                                                                              -65.1255                                                                            0.135                                                                              -82.1664                                                                            0.042                                                                              -94.4518                                                                            0   -100                                            0.173                                                                              -78.3479                                                                            0.081                                                                              -89.8623                                                                            0   -100 0   -100                                            0.212                                                                              -73.8272                                                                            0.082                                                                              -89.8765                                                                            0   -100 0   -100                                            Mean ± S.D.                                                                 0.219                                                                              -71.989                                                                             0.093                                                                              -88.044                                                                             0.007                                                                              -99.079                                                                             0.000                                                                              -100.000                                        0.053                                                                              7.837                                                                               0.049                                                                              6.662                                                                               0.014                                                                              1.817                                                                               0.000                                                                              0.000                                           __________________________________________________________________________     Day 18       Day 21      Day 23                                                area % variat.                                                                              area % variat.                                                                             area % variat.                                        __________________________________________________________________________     0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             0    -100    0    -100   0    -100                                             Mean ± S.D.                                                                 0    -100.000                                                                               0    -100   0    -100                                             0.000                                                                               0.000   0.000                                                                               0.000  0.000                                                                               0.000                                            __________________________________________________________________________

                                      TABLE 3D                                     __________________________________________________________________________     Wound healing data - Experiment 3                                              Component B (004-001) 2μg                                                   __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7   Day 9   Day 11                             area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                       __________________________________________________________________________     0.776                                                                              0.591                                                                             -23.8402                                                                            0.577                                                                             -25.6443                                                                            0.285                                                                             -63.6943                                                                            0.202                                                                             -74.2675                                                                             0.173                                                                            -77.7062                                                                            0.063                                                                             -91.8814                        0.785                                                                              0.548                                                                             -30.1911                                                                            0.447                                                                             -43.0573                                                                            0.357                                                                             -53.9948                                                                            0.309                                                                             -60.1804                                                                             0.229                                                                            -70.828                                                                             0.093                                                                             -88.1529                        0.776                                                                              0.68                                                                              -12.3711                                                                            0.587                                                                             -24.3557                                                                            0.435                                                                             -44.0874                                                                            0.319                                                                             -58.9974                                                                            0.246                                                                             -68.299                                                                             0.056                                                                             -92.7835                        0.778                                                                              0.498                                                                             -35.990                                                                             0.194                                                                             -75.0643                                                                            0.179                                                                             -76.933                                                                             0.112                                                                             -85.567                                                                             0.107                                                                             -86.2468                                                                            0  -100                            0.776                                                                              0.428                                                                             -44.845                                                                             0.183                                                                             -76.4175                                                                            0.152                                                                             -81.071                                                                             0.092                                                                             -88.543                                                                             0.008                                                                             -98.9691                                                                            0  -100                            0.803                                                                              0.638                                                                             -20.548                                                                             0.597                                                                             -25.6538                                                                            0.427                                                                             -44.183                                                                             0.365                                                                             -52.2876                                                                            0.141                                                                             -82.4408                                                                            0.08                                                                              -90.0374                        0.765                                                                              0.72                                                                              -5.882                                                                              0.657                                                                             -14.1176                                                                            0.496                                                                             -41.3018                                                                            0.357                                                                             -57.7515                                                                            0.316                                                                             -58.6928                                                                            0.181                                                                             -76.3399                        0.845                                                                              0.591                                                                             -30.059                                                                             0.512                                                                             -39.4083                                                                            0.427                                                                             -47.284                                                                             0.337                                                                             -58.3951                                                                            0.196                                                                             -76.8047                                                                            0.086                                                                             -89.8225                        0.81                                                                               0.669                                                                             -17.407                                                                             0.567                                                                             -30  0.518                                                                             -36.0494                                                                            0.355                                                                             -56.1728                                                                            0.28                                                                              -65.4321                                                                            0.188                                                                             -76.7901                        0.834                                                                              0.631                                                                             -24.341                                                                             0.469                                                                             -43.765                                                                             0.316                                                                             -60.2416                                                                            0.233                                                                             -70.6844                                                                            0.153                                                                             -81.1111                                                                            0.008                                                                             -99.0408                        __________________________________________________________________________     Mean ± S.D.                                                                 0.7948                                                                             0.599                                                                             -24.547                                                                             0.479                                                                             -39.748                                                                             0.359                                                                             -54.884                                                                             0.268                                                                             -66.285                                                                             0.185                                                                             -76.653                                                                             0.076                                                                             -90.485                         0.027                                                                              0.089                                                                             11.398                                                                              0.165                                                                             21.096                                                                              0.125                                                                             15.301                                                                              0.103                                                                             12.797                                                                              0.090                                                                             11.531                                                                              0.067                                                                             8.532                           __________________________________________________________________________                 Day 14  Day 16  Day 18  Day 21  Day 23                                         area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                       __________________________________________________________________________                 0  -100 0  -100    -100 0  -100 0  -100            0                           0  -100 0  -100    -1000                                                                               0  -100 0  -100                                        0.007                                                                             -99.0979                                                                            0  -100    -100 0  -100 0  -100                                        0  -100 0  -100    -1000                                                                               0  -100 0  -100                                        0  -100 0  -100    -1000                                                                               0  -100 0  -100                                        0  -100 0  -100    -1000                                                                               0  -100 0  -100                                        0.114                                                                             -85.098                                                                             0  -100    -100 0  -100 0  -100                                        0  -100 0  -100    -1000                                                                               0  -100 0  -100                                        0.106                                                                             -86.9136                                                                            0.053                                                                             -93.4568                                                                               -100 0  -100 0  -100                                        0  -100 0  -100    -100 0  -100 0  -100                            __________________________________________________________________________                 Mean ± S.D.                                                                 0.023                                                                             -97.111                                                                             0.005                                                                             -99.346                                                                             0.000                                                                             -100.000                                                                            0.000                                                                             -100.000                                                                            0.000                                                                             -100.000                                    0.046                                                                             5.875                                                                               0.017                                                                             2.069                                                                               0.000                                                                             0.000                                                                               0.000                                                                             0.000                                                                               0.000                                                                             0.000                           __________________________________________________________________________

                                      TABLE 3E                                     __________________________________________________________________________     Wound healing data - Experiment 3                                              Component B (004-001) 1 mg/kg, i.v.                                            __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7   Day 9   Day 11                             area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                       __________________________________________________________________________     0.702                                                                              0.532                                                                             -24.2165                                                                            0.233                                                                             -66.8091                                                                            0.159                                                                             -77.3504                                                                            0.18                                                                              -74.359                                                                             0.106                                                                             -84.9003                                                                            0.012                                                                             -98.2906                        0.713                                                                              0.545                                                                             -23.5624                                                                            0.401                                                                             -43.7588                                                                            0.321                                                                             -54.979                                                                             0.311                                                                             -56.3815                                                                            0.229                                                                             -67.8822                                                                            0.088                                                                             -87.6578                        0.854                                                                              0.731                                                                             -14.4028                                                                            0.608                                                                             -28.8056                                                                            0.447                                                                             -47.6581                                                                            0.43                                                                              -49.6487                                                                            0.324                                                                             -62.0609                                                                            0.127                                                                             -85.1288                        0.698                                                                              0.597                                                                             -14.470                                                                             0.421                                                                             -39.6848                                                                            0.321                                                                             -54.0115                                                                            0.297                                                                             -57.4499                                                                             0.204                                                                            -70.7736                                                                            0.027                                                                             -96.1318                        0.702                                                                              0.591                                                                             -15.812                                                                             0.459                                                                             -34.6154                                                                            0.329                                                                             -53.1339                                                                            0.301                                                                             -57.1225                                                                             0.137                                                                            -80.4843                                                                            0.043                                                                             -93.8746                        0.791                                                                              0.529                                                                             -33.123                                                                             0.433                                                                             -45.2592                                                                            0.329                                                                             -58.4071                                                                            0.263                                                                             -66.7509                                                                             0.137                                                                            -82.6802                                                                            0.008                                                                             -98.9886                        0.799                                                                              0.611                                                                             -23.529                                                                             0.387                                                                             -51.5645                                                                            0.231                                                                             -71.0889                                                                            0.113                                                                             -85.8573                                                                            0.053                                                                             -93.3667                                                                            0  -100                            0.842                                                                              0.791                                                                             -6.057                                                                              0.462                                                                             -45.1306                                                                            0.418                                                                             -50.3563                                                                            0.352                                                                             -58.1948                                                                             0.307                                                                            -63.5392                                                                            0.138                                                                             -83.6105                        0.834                                                                              0.628                                                                             -24.700                                                                             0.481                                                                             -42.3261                                                                            0.393                                                                             -52.8777                                                                            0.311                                                                             -62.7098                                                                             0.2                                                                              -76.0192                                                                            0.072                                                                             -91.3669                        0.886                                                                              0.818                                                                             -7.675                                                                              0.694                                                                             -21.6704                                                                            0.55                                                                              -37.9233                                                                            0.54                                                                              -39.0519                                                                            0.39                                                                              -55.9819                                                                            0.212                                                                             -76.0722                        __________________________________________________________________________     Mean ± S.D.                                                                 0.7821                                                                             0.637                                                                             -18.755                                                                             0.458                                                                             -41.962                                                                             0.350                                                                             -55.779                                                                             0.310                                                                             -60.753                                                                             0.209                                                                             -73.769                                                                             0.073                                                                             -91.112                         0.072                                                                              0.106                                                                             8.482                                                                               0.125                                                                             12.373                                                                              0.110                                                                             11.255                                                                              0.119                                                                              12.906                                                                             0.106                                                                             11.734                                                                              0.069                                                                             7.858                           __________________________________________________________________________                 Day 14  Day 16  Day 18  Day 21  Day 23                                         area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                       __________________________________________________________________________                 0  -100 0  -100    -100 0  -100 0  0                                                                              -100                                        0  -100 0  -100    -100 0  -100 0  -100                                        0.007                                                                             -99.1803                                                                            0.008                                                                             -99.0632                                                                               0                                                                              -100 0  -100 0  -100                                        0  -100 0  -100    -100 0  -100 0  -100                                        0  -100 0  -100    -100 0  -100 0  -100                                        0  -100 0  -100    -100 0  -100 0  -100                                        0  -100 0  -100    -100 0  -100 0  -100                                        0.011                                                                             -98.6936                                                                            0  -100    -100 0  -100 0  -100                                        0  -100 0  -100    -100 0  -100 0  -100                                        0.013                                                                             -98.5327                                                                            0  -100   0                                                                               -100 0  -100 0  -100                            __________________________________________________________________________                 Mean ± S.D.                                                                 0.003                                                                             -99.641                                                                             0.001                                                                             -99.906                                                                             0.000                                                                             -100.000                                                                            0.000                                                                             -100.000                                                                            0.000                                                                             -100.000                                    0.005                                                                             0.600                                                                               0.003                                                                             0.296                                                                               0.000                                                                             0.000                                                                               0.000                                                                             0.000                                                                               0.000                                                                             0.000                           __________________________________________________________________________

                                      Table 4A                                     __________________________________________________________________________     Wound healing data - Experiment 4                                              Phosphate buffer                                                               __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7   Day 9   Day 11                             area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                       __________________________________________________________________________     0.813                                                                              0.817                                                                             0.492005                                                                            0.785                                                                             -3.44403                                                                            0.393                                                                             -51.6605                                                                            0.297                                                                             -63.4686                                                                               -66.9127.269                                                                        0.173                                                                             -78.7208                        0.813                                                                              0.809                                                                             -0.492                                                                              0.817                                                                             0.492005                                                                            0.462                                                                             -43.1734                                                                            0.541                                                                             -33.4563                                                                               -63.0996                                                                            0.19                                                                              -76.6298                        0.954                                                                              0.981                                                                             2.830189                                                                            0.912                                                                             -4.40252                                                                            0.672                                                                             -29.5597                                                                            0.584                                                                             -38.7841                                                                               0.481                                                                          -49.5807                                                                            0.407                                                                             -57.3375                        0.833                                                                              0.821                                                                             -1.441                                                                              0.716                                                                             -14.0456                                                                            0.48                                                                              -42.377                                                                             0.404                                                                             -51.5006                                                                               -58.5834                                                                            0.264                                                                             -68.3073                        0.841                                                                              0.882                                                                             4.875                                                                               0.878                                                                             4.399524                                                                            0.758                                                                             -9.8692                                                                             0.694                                                                             -17.4792                                                                               0.522                                                                          -37.931                                                                             0.271                                                                             -67.7765                        0.813                                                                              0.805                                                                             -0.984                                                                              0.608                                                                             -25.2153                                                                            0.407                                                                             -49.9385                                                                            0.393                                                                             -51.6605                                                                               -65.1907                                                                            0.289                                                                             -64.4526                        0.805                                                                              0.821                                                                             1.988                                                                               0.746                                                                             -7.32919                                                                            0.544                                                                             -32.4224                                                                            0.444                                                                             -44.8447                                                                               -55.1553                                                                            0.285                                                                             -64.5963                        0.769                                                                              0.825                                                                             7.282                                                                               0.762                                                                             -0.91027                                                                            0.69                                                                              -10.2731                                                                            0.657                                                                             -14.5644                                                                               -38.6216                                                                            0.311                                                                             -59.5579                        0.845                                                                              0.874                                                                             3.432                                                                               0.845                                                                             0    0.639                                                                             -24.3787                                                                            0.636                                                                             -24.7337                                                                               -55.7396                                                                            0.352                                                                             -58.3432                        0.817                                                                              0.829                                                                             1.469                                                                               0.789                                                                             -3.42717                                                                            0.496                                                                             -39.2901                                                                            0.387                                                                             -52.6316                                                                               0.246                                                                          -69.8898                                                                            0.261                                                                             -68.0539                        __________________________________________________________________________     Mean ± S.D.                                                                 0.830                                                                              0.846                                                                             1.945                                                                               0.786                                                                             -5.388                                                                              0.554                                                                             -33.294                                                                             0.504                                                                             -39.312                                                                             0.365                                                                             -56.070                                                                             0.280                                                                             -66.378                         0.8303                                                                             0.054                                                                             2.757                                                                               0.087                                                                             8.563                                                                               0.127                                                                             14.919                                                                              0.136                                                                             16.428                                                                                0.097                                                                           11.175                                                                              0.069                                                                              7.193                          __________________________________________________________________________                 Day 14  Day 16  Day 18  Day 21  Day 23                                         area                                                                              % variant.                                                                          area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                       __________________________________________________________________________                 0.125                                                                             -84.6248                                                                            0.091                                                                             -88.8069                                                                               -91.2669                                                                            0.009                                                                             -98.893                                                                             0  -100                                        0.182                                                                             -77.6138                                                                            0.062                                                                             -92.3739                                                                               -94.5879                                                                            0  -100 0  -100                                        0.365                                                                             -61.74                                                                              0.227                                                                             -76.2055                                                                               -89.6226                                                                            0.27                                                                              -71.6981                                                                            0  -100                                        0.239                                                                             -71.3085                                                                            0.112                                                                             -86.5546                                                                               -91.3565                                                                            0  -100 0  -100                                        0.173                                                                             -79.4293                                                                            0.137                                                                             -83.7099                                                                               -89.0606                                                                            0.031                                                                             -96.3139                                                                            0  -100                                        0.168                                                                             -79.3358                                                                            0.124                                                                             -84.7478                                                                               -91.5129                                                                            0  -100 0  -100                                        0.214                                                                             -73.4161                                                                            0.074                                                                             -90.8075                                                                               -94.6584                                                                            0  -100 0  -100                                        0.271                                                                             -64.7594                                                                            0.155                                                                             -79.844                                                                                -95.9688                                                                            0.28                                                                              -63.5891                                                                            0  -I00                                        0.264                                                                             -68.7574                                                                            0.148                                                                             -82.4852                                                                               -94.4379                                                                            0  -100 0  -100                                        0.19                                                                              -76.7442                                                                            0.112                                                                             -86.2913                                                                               -91.9217                                                                            0.008                                                                             -99.0208                                                                            0  -100                            __________________________________________________________________________                 Mean ± S.D.                                                                 0.219                                                                             -73.773                                                                             0.124                                                                             -85.183                                                                             0.063                                                                             -92.439                                                                             0.060                                                                             -92.951                                                                             0.000                                                                             -100.000                                    0.069                                                                             7.162                                                                               0.047                                                                             4.925                                                                               0.022                                                                             2.334                                                                               0.114                                                                             13.522                                                                              0.000                                                                              0.000                          __________________________________________________________________________

                                      TABLE 4B                                     __________________________________________________________________________     Wound healing data - Experiment 4                                              Bovine Serum Albumin                                                           __________________________________________________________________________     Day 0                                                                              Day 1   Day 3   Day 5   Day 7                                              area                                                                               area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                                                           area                                                                              % variat.                                       __________________________________________________________________________     0.785                                                                              0.821                                                                             4.585987                                                                            0.805                                                                               2.547771                                                                          0.765                                                                              -2.54777                                                                           0.622                                                                             -20.7643                                        0.857                                                                              0.858                                                                             0.116686                                                                            0.786                                                                             -8.28471                                                                            0.65                                                                              -24.154                                                                             0.625                                                                             -27.0712                                        0.837                                                                              0.874                                                                             4.42055                                                                             0.825                                                                             -1.43369                                                                            0.746                                                                             -10.8722                                                                            0.544                                                                             -35.006                                         0.781                                                                              0.817                                                                             4.609475                                                                            0.794                                                                               1.664533                                                                          0.708                                                                              -9.34699                                                                           0.611                                                                             -21.767                                         0.853                                                                              0.924                                                                             8.323564                                                                            0.882                                                                               3.399766                                                                          0.735                                                                             -13.8335                                                                            0.668                                                                             -21.6882                                        0.845                                                                              0.895                                                                             5.91716                                                                             0.785                                                                             -7.10059                                                                            0.727                                                                             -13.9645                                                                            0.618                                                                             -26.8639                                        0.833                                                                              0.893                                                                             7.202881                                                                            0.878                                                                               5.402161                                                                          0.675                                                                             -18.9676                                                                            0.453                                                                             -45.6182                                        0.854                                                                              0.916                                                                             7.259953                                                                            0.899                                                                               5.269321                                                                          0.712                                                                             -16.6276                                                                            0.48                                                                              -43.7939                                        __________________________________________________________________________     Mean ± S.D.                                                                 0.831                                                                              0.875                                                                             5.305                                                                               0.832                                                                             0.183                                                                               0.715                                                                             -13.789                                                                             0.578                                                                             -30.322                                         0.031                                                                              0.040                                                                             2.553                                                                               0.047                                                                             5.327                                                                               0.038                                                                                6.513                                                                            0.077                                                                                9.993                                        __________________________________________________________________________     Day 9   Day 11   Day 14    Day 16                                              area                                                                              % variat.                                                                           area                                                                              % variat.                                                                            area                                                                               % variat.                                                                            area                                                                               % variat.                                       __________________________________________________________________________     0.538                                                                             -31.465                                                                             0.344                                                                             -56.1783                                                                             0.244                                                                              -68.9172                                                                             0.169                                                                              -78.4713                                        0.557                                                                             -35.0058                                                                            0.368                                                                             -57.0595                                                                             0.329                                                                              -61.6103                                                                             0.162                                                                              -81.0968                                        0.413                                                                             -50.6571                                                                            0.287                                                                             -65.7109                                                                             0.226                                                                              -72.9988                                                                             0.101                                                                              -87.9331                                        0.554                                                                             -29.0653                                                                            0.329                                                                             -57.8745                                                                             0.259                                                                              -66.8374                                                                             0.138                                                                              -82.3303                                        0.448                                                                             -47.4795                                                                            0.352                                                                             -58.7339                                                                             0.239                                                                              -71.9812                                                                             0.173                                                                              -79.7186                                        0.561                                                                             -33.6095                                                                            0.299                                                                             -64.6154                                                                             0.255                                                                              -69.8225                                                                             0.21                                                                               -75.1479                                        0.314                                                                             -62.3049                                                                            0.255                                                                             -69.3878                                                                             0.22                                                                               -73.5894                                                                             0.166                                                                              -80.072                                         0.404                                                                             -52.6932                                                                            0.266                                                                             -68.8525                                                                             0.239                                                                              -72.0141                                                                             0.166                                                                              -80.5621                                        __________________________________________________________________________     Mean ± S.D.                                                                 0.474                                                                             -42.785                                                                             0.313                                                                             -62.302                                                                              0.251                                                                              -69.721                                                                              0.161                                                                              -80.667                                         0.092                                                                               12.097                                                                            0.042                                                                                5.443                                                                             0.034                                                                                 3.979                                                                             0.031                                                                                 3.631                                        __________________________________________________________________________     Day 18  Day 21   Day 23    Day 25                                              area                                                                              % variat.                                                                           area                                                                              % variat.                                                                            area                                                                               % variat.                                                                            area                                                                               % variat.                                       __________________________________________________________________________     0.062                                                                              -92.1019                                                                           0.007                                                                              -99.1083                                                                            0   -100  0   -100                                            0.039                                                                              -95.4492                                                                           0.021                                                                              -97.5496                                                                            0   -100  0   -100                                            0  -100 0.000                                                                             -100  0   -100  0   -100                                            0.081                                                                              -89.6287                                                                           0.031                                                                              -96.0307                                                                            0   -100  0   -100                                            0.094                                                                              -88.9801                                                                           0.055                                                                              -93.5522                                                                            0.018                                                                               -97.8898                                                                            0   -100                                            0.145                                                                              -82.8402                                                                           0  -100  0   -100  0   -100                                            0.083                                                                              -90.036                                                                            0.008                                                                              -99.0396                                                                            0   -100  0   -100                                            0.107                                                                              -87.4707                                                                           0  -100  0   -I00  0   -100                                            __________________________________________________________________________     Mean ± S.D.                                                                 0.076                                                                             -90.813                                                                             0.015                                                                             -98.160                                                                              0.002                                                                              -99.736                                                                              0.000                                                                              -100.000                                        0.044                                                                                5.178                                                                            0.020                                                                                2.329                                                                             0.006                                                                                 0.746                                                                             0.000                                                                                 0.000                                        __________________________________________________________________________ 

We claim:
 1. Method of treatment of wounds, ulcers and other traumatic lesions to any of the tissues in the body, comprising administering an effective amount of Component B, together with a pharmaceutically acceptable carrier. 